In enantioselective reactions, the major, desired enantiomer is commonly obtained along with the minor, undesired enantiomer. By continuous recycling of this undesired enantiomer back to starting material, products with improved enantiomeric purity can be obtained. Such in situ minor enantiomer recycling can be accomplished by coupling the catalytic reaction to an exergonic transformation of a sacrificial reagent. The method has been applied to the synthesis of O-acylated cyanohydrins, which serve as starting materials for a variety of biologically active compounds.
O-Acylated cyanohydrins are versatile compounds, which in comparison to the unprotected cyanohydrins are stable towards racemization and decomposition. In addition they are important intermediates in the synthesis of a variety of compounds with biological properties [1–4], and in some cases they serve as versatile target compounds [5–8]. Procedures providing access to racemic O-acylated cyanohydrins have been known since the middle of the last century , and more recently several alternative procedures have been developed [10–12]. Enantioselective methods were, however, unknown before 2005, when we developed a direct route to enantioenriched acylated cyanohydrins from prochiral aldehydes and acyl cyanides catalyzed by a dual activation system consisting of a Lewis acid and a Lewis base [13, 14]. At about the same time, Baeza et al.  used a different catalytic system in an alternative method, which however was limited to reactions with aroyl cyanides. In our process, the Lewis acid, which is a dimeric titanium salen complex , activates the aldehyde, while the Lewis base, a tertiary amine such as Et3N, DABCO, sparteine, or cinchonidine, activates the nucleophile as well as the electrophile. A simplified mechanism is shown in Scheme 1 .
In reactions with non-activated aldehydes, attack of cyanide is rate-limiting and the chiral induction relies on the presence of a chiral non-racemic Lewis acid, whereas in reactions with electron deficient aldehydes, acylation of the titanium alcoholate is the slow step; in the latter case formation of product with high enantiomeric purity requires a catalytic system consisting of both chiral non-racemic Lewis acid and Lewis base .
Enantiomeric ratios up to 98:2 were observed with a variety of combinations of aldehydes and acyl cyanides. However, in reactions with aldehydes that gave products prone to base-catalyzed racemization, the enantiomeric purity of the products was often considerably lower. Since highly enantioenriched compounds are required for a variety of applications, purification of the primarily formed products may be necessary, a situation often encountered in enantioselective synthesis. Purification may be accomplished by e.g. recrystallization or kinetic resolution, whereby the minor enantiomer is transformed to some compound which more easily can be separated from the product. Although enantiopure product may be obtained by kinetic resolution, the process inevitably leads to a reduction of the yield. Therefore in situ recycling of the undesired enantiomer to prochiral starting material would be a highly desirable option.
Minor enantiomer recycling (MER)
In situ recycling, i.e. transformation of achiral starting material A to a mixture of enantiomers R and S, where R is the major, desired enantiomer and S the minor, undesired enantiomer, and reformation of starting material by transformation of S to A by a second catalyst may be achieved by means of an exergonic process X–>Y coupled to the catalytic reaction, such that the entire process becomes thermodynamically favored (Scheme 2).
Acylcyanation of prochiral aldehydes was identified as a suitable model reaction for a minor enantiomer recycling process: we had access to an efficient catalytic system for the forward reaction, and the reverse reaction, the selective hydrolysis of the (S)-enantiomer, was known to be catalyzed by Candida antarctica lipase B (CALB) . In the presence of the two catalysts, (S,S)-Ti and CALB, using a two-phase system consisting of toluene and aqueous buffer pH 7–8, the desired cyclic process could be accomplished . Under the conditions employed, no Lewis base was required, and consequently racemization of base-sensitive compounds was not a problem. To avoid hydrolysis of the hydrolytically sensitive acyl cyanide, the reagent is slowly added into the organic phase using a syringe pump. The cyclic process consists of an enantioselective forward reaction and kinetic resolution of the product. It is characterized by not only increasing yield over time, but also by steadily increasing ee . The two catalysts used for the forward and reverse reactions reinforce each other, which results in an enantioselectivity which is higher that that of any of the single steps.
Reaction of benzaldehyde proceeded uneventfully under these conditions to give (R)-O-acetyl mandelonitrile in 98% yield and with >99% ee (Scheme 3) . This can be compared to the Lewis acid-Lewis base catalyzed forward reaction which gave the product in 89% yield and with 94% ee, as well as with alternative processes, such as reaction of benzaldehyde with KCN in the presence of excess acetic anhydride, which resulted in 92% yield and 89% ee , scandium(III)-catalyzed transformation of silylated cyanohydrin by acetic anhydride, which gave 98% of the product with 83% ee (when starting from silylated derivative with 84% ee) , and dynamic kinetic resolution with a biocatalyst, which gave 97% yield and 98% ee . This comparison serves to demonstrate the usefulness of the cyclic process.
Biocatalyzed reactions often suffer from the unavailability of a catalyst producing the opposite product enantiomer. However, Candida rugosa lipase (CRL) is known to hydrolyze the (R)-enantiomer of O-acetyl mandelonitrile . Thus, by using the (R,R)-enantiomer of the titanium complex and replacing CALB by CRL, (S)-O-acetyl mandelonitrile was obtained.
The product from acetylcyanation of acrolein serves as an intermediate in the synthesis of glyfosinate . The product is prone to racemization under basic conditions. As a consequence, Lewis acid–Lewis base catalyzed acetylcyanation affords a product which partially racemizes during work-up . The analogous reaction with crotyl aldehyde gave the product in 78% yield and with 94% ee, but upon warming the reaction mixture to room temperature, the ee deteriorated . Treatment of the scalemic product with CALB resulted in Kinetic Resolution (KR) and gave a product with improved enantiomeric purity, 98% ee, but at the expense of the yield, which decreased to 69% (A, Scheme 4); the decrease is dependent on the selectivity, E, i.e. the ratio of the rate constants for hydrolysis of the two enantiomers. By instead using minor enantiomer recycling (MER), i.e. a combination of the titanium salen complex and CALB in a two-phase system, racemization could be avoided and the product was isolated in close to quantitative yield and with >99% ee; no decrease in ee was observed during work-up (B, Scheme 4). The same substrate was also subjected to Dynamic Kinetic Resolution (DKR) consisting of reversible formation of racemic cyanohydrin by acetone cyanohydrin and selective acylation of the (S)-enantiomer by isopropenyl acetate catalyzed by CALB (C, Scheme 4). Since the enzyme catalyzes the hydrolysis of the (S)-enantiomer in the MER process and acylation of the same enantiomer in DKR, products with opposite absolute configuration are obtained in the two processes.
In the following the advantage of MER will be illustrated by some synthetic examples where the product is formed in low yield and/or low ee by other enantioselective methods.
We envisaged that O-protected cyanohydrins from suitable aldehydes would serve as efficient starting materials for the preparation of amino alcohols, e.g. β-blockers such as (S)-propranolol. This route did not seem to have been explored, however. A possible explanation is that the required cyanohydrin is obtained with low enantiomeric purity; the Lewis acid-Lewis base catalyzed process gave the product with merely 15% ee. Improved results were observed by minor enantiomer recycling, which gave the product with 96% ee in 61% yield; the moderate yield obtained was due to decomposition of the aldehyde under the reaction conditions (Scheme 5) . By allowing enzymatic hydrolysis to continue after completed addition of acetyl cyanide, kinetic resolution of the product results in improved ee of 99.7%, but evidently at the same time in somewhat decreased yield. The desired product, after the required functional group transformations, was isolated with 97% ee.
By using the same procedure, (R)-dichloroisoproterenol and (R)-pronethalol were prepared with 99 and 97% ee, respectively.
The range of acyl cyanides which can be used in minor enantiomer recycling is limited by the properties of the enzyme; acyl groups with more than five carbon atoms are not hydrolyzed by CALB. However, by employing α-bromoacetyl and α-bromopropionyl cyanide as reagents, products with reactive handles for subsequent synthetic transformations were obtained . Reactions in the presence of amine gave low yields as a result of reaction of the amine with the activated halide. However, since no tertiary amine is required under minor enantiomer recycling conditions, reaction of benzaldehyde with racemic 2-bromopropionyl cyanide under these conditions proceeded to give a high yield of a mixture of four stereoisomers, two of which were hydrolyzed by CALB. Consequently, completed reaction gave a diastereomeric mixture of two stereoisomers, both with (R)-configuration at the newly formed stereogenic center (Scheme 6).
The diastereomeric product mixture was subjected to the Blaise conditions . Thus, treatment of the acylated cyanohydrins derived from benzaldehyde with Zn, followed by aqueous ammonium chloride, provided access to highly enantioenriched aminofuranones (Scheme 7) . Many compounds of this type exhibit interesting biological properties [31, 32] and have therefore been the focus of extensive synthetic efforts .
Starting from other aldehydes, a range of highly enantioenriched aminofuranones were obtained (Fig. 1).
Reaction of the acylated cyanohydrins possessing a reactive handle with nitrogen nucleophiles provides synthetic routes for other types of compounds. Particularly interesting results were obtained by substitution of the bromide with anilines (Scheme 8) . Reduction of the primarily obtained product, with accompanying acyl transfer from oxygen to nitrogen, using hydrogen/Raney nickel gave N-acylated amino alcohols. The reduction proceeded with essentially no loss of enantiomeric purity, but unfortunately in low yields, most probably as a result of cleavage of benzylic bonds.
This procedure was identified as a suitable route to various biologically active compounds, such as midrodine and solabegron. The latter compound contains a N-(2-ethylamino)-β-amino alcohol structural motif, accessible by reduction of the amide function. It is a β3-adrenergic receptor agonist, which has been developed for treatment of overactive bladder and irritable bowel syndrome .
Due to the expected utility of solabegron, our synthetic sequence was applied to the synthesis of this compound (Scheme 9). For this purpose, 3-chlorobenzaldehyde was used as starting aldehyde. Acylcyanation under minor enantiomer recycling conditions, followed by substitution with the appropriate aniline and reduction gave a crucial intermediate with 94% ee. Final functional group transformations afforded the target compound.
By minor enantiomer recycling (MER), O-acylated cyanohydrins are obtained in high yields and with high enantiomeric purity, even from substrates that give poor results employing other methods. In contrast to sequential processes, MER can lead to high yields and result in high enantioselectivities even when two mediocre chiral catalysts are combined. The cyclic method is particularly valuable in cases when the product undergoes facile racemization and for the preparation of products which due to side reactions are not compatible with the conditions used for alternative processes. The products obtained serve as useful starting materials for a variety of biologically active compounds.
A collection of invited papers based on presentations at the 19th European Symposium on Organic Chemistry (ESOC-19), Lisbon, Portugal, 12–16 July 2015.
The work described in this review is the result of highly dedicated work by a number of students: Dr Stina Lundgren, Dr Erica Wingstrand, Dr Maël Penhoat, Dr Anna Laurell Nash, Dr Robin Hertzberg, Dr Ye-Qian Wen, Dr Khalid Widyan, Ms Inanllely Gonzalez, and Mr Guillermo Montreal Santiago – I am indepted to their hard work, skill, and enthusiasm. I also want to thank professor Karl Hult, Dr Linda Fransson, professor Tore Brinck, and Mr Björn Dahlgren for fruitful collaborations.
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